The effects of mitochondrial dysfunction on the cell cycle

Hyperproliferative disorders, such as pulmonary arterial hypertension (PAH) and cancers, are characterized by excessive cell proliferation and resistance to apoptosis (Dasgupta et al., 2021). This “neoplastic phenotype” is due, at least in part, to acquired changes in mitochondrial metabolism. While perturbation of mitochondrial metabolism, notably a shift to aerobic glycolysis (Warburg phenomenon) contributes to the proliferation/apoptosis imbalance in cells from hyperproliferative disease origin, a newly recognized abnormality, namely, dysregulation of mitochondrial dynamics has been identified (Rehman et al., 2012). Mitochondria continuously join together (fusion) and divide (fission) thereby maintaining network quality control (Mao and Klionsky, 2013), mediating cell death (Tian et al., 2017) and regulating metabolism and the cell cycle (Chen et al., 2018). The major mediator of mitochondrial fission is dynamin-related protein 1 (Drp1); while fusion is meditated by mitofusin-1 and mitofusin-2 (Archer, 2013). Upon activation, Drp1 is recruited from the cytosol to the mitochondrial outer membrane (OMM) via interaction with its receptor proteins in a poorly understood multimerization reaction. In mammals, there are four proteins on the mitochondrial outer membrane that act as Drp1 receptors: mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively) (Atkins et al., 2016). Mitotic fission coordinates mitochondrial and nuclear division, ensuring equitable distribution of mitochondria between daughter cells. Mitotic fission occurs via a Drp1-dependent process. Several studies have shown that inhibition of mitotic fission triggers a cell cycle checkpoint and results in cell cycle arrest and apoptosis (Chen et al., 2018) both in cancers and in non-malignant, hyperproliferative diseases such as PAH (Marsboom et al., 2012). Thus, mitotic fission is an appealing therapeutic target. It has also been shown that Drp1 expression is upregulated in hyperproliferative diseases and Drp1 is postranslationally activated (Marsboom et al., 2012; Rehman et al., 2012; Tian et al., 2018; Abu-Hanna et al., 2023). Inhibition of Drp1 regresses cancer and PAH in animal models (Marsboom et al., 2012; Rehman et al., 2012). In this special edition of Frontiers in Cell and Developmental Biology, four journal articles on The effects of mitochondrial dysfunction on the cell cycle were published: Two original research articles, one review, and one mini-review. Three articles are relevant to pulmonary hypertension (PH), and the other is related to diabetes